TY - JOUR
T1 - The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes
AU - Huether, Robert
AU - Dong, Li
AU - Chen, Xiang
AU - Wu, Gang
AU - Parker, Matthew
AU - Wei, Lei
AU - Ma, Jing
AU - Edmonson, Michael N.
AU - Hedlund, Erin K.
AU - Rusch, Michael C.
AU - Shurtleff, Sheila A.
AU - Mulder, Heather L.
AU - Boggs, Kristy
AU - Vadordaria, Bhavin
AU - Cheng, Jinjun
AU - Yergeau, Donald
AU - Song, Guangchun
AU - Becksfort, Jared
AU - Lemmon, Gordon
AU - Weber, Catherine
AU - Cai, Zhongling
AU - Dang, Jinjun
AU - Walsh, Michael
AU - Gedman, Amanda L.
AU - Faber, Zachary
AU - Easton, John
AU - Gruber, Tanja
AU - Kriwacki, Richard W.
AU - Partridge, Janet F.
AU - Ding, Li
AU - Wilson, Richard K.
AU - Mardis, Elaine R.
AU - Mullighan, Charles G.
AU - Gilbertson, Richard J.
AU - Baker, Suzanne J.
AU - Zambetti, Gerard
AU - Ellison, David W.
AU - Zhang, Jinghui
AU - Downing, James R.
N1 - Funding Information:
This study was supported by the American Lebanese Syrian Associated Charities (ALSAC) of St Jude Children’s Research Hospital and CA096832. This research was supported by the members of the St Jude Children’s Research Hospital–Washington University Pediatric Cancer Genome Project. We thank P. Nagajawatte for technical assistance in submitting the capture data to EBI.
Publisher Copyright:
© 2014 Macmillan Publishers Limited. All rights reserved.
PY - 2014/4/8
Y1 - 2014/4/8
N2 - Studies of paediatric cancers have shown a high frequency of mutation across epigenetic regulators. Here we sequence 633 genes, encoding the majority of known epigenetic regulatory proteins, in over 1,000 paediatric tumours to define the landscape of somatic mutations in epigenetic regulators in paediatric cancer. Our results demonstrate a marked variation in the frequency of gene mutations across 21 different paediatric cancer subtypes, with the highest frequency of mutations detected in high-grade gliomas, T-lineage acute lymphoblastic leukaemia and medulloblastoma, and a paucity of mutations in low-grade glioma and retinoblastoma. The most frequently mutated genes are H3F3A, PHF6, ATRX, KDM6A, SMARCA4, ASXL2, CREBBP, EZH2, MLL2, USP7, ASXL1, NSD2, SETD2, SMC1A and ZMYM3. We identify novel loss-of-function mutations in the ubiquitin-specific processing protease 7 (USP7) in paediatric leukaemia, which result in decreased deubiquitination activity. Collectively, our results help to define the landscape of mutations in epigenetic regulatory genes in paediatric cancer and yield a valuable new database for investigating the role of epigenetic dysregulations in cancer.
AB - Studies of paediatric cancers have shown a high frequency of mutation across epigenetic regulators. Here we sequence 633 genes, encoding the majority of known epigenetic regulatory proteins, in over 1,000 paediatric tumours to define the landscape of somatic mutations in epigenetic regulators in paediatric cancer. Our results demonstrate a marked variation in the frequency of gene mutations across 21 different paediatric cancer subtypes, with the highest frequency of mutations detected in high-grade gliomas, T-lineage acute lymphoblastic leukaemia and medulloblastoma, and a paucity of mutations in low-grade glioma and retinoblastoma. The most frequently mutated genes are H3F3A, PHF6, ATRX, KDM6A, SMARCA4, ASXL2, CREBBP, EZH2, MLL2, USP7, ASXL1, NSD2, SETD2, SMC1A and ZMYM3. We identify novel loss-of-function mutations in the ubiquitin-specific processing protease 7 (USP7) in paediatric leukaemia, which result in decreased deubiquitination activity. Collectively, our results help to define the landscape of mutations in epigenetic regulatory genes in paediatric cancer and yield a valuable new database for investigating the role of epigenetic dysregulations in cancer.
UR - http://www.scopus.com/inward/record.url?scp=84907304074&partnerID=8YFLogxK
U2 - 10.1038/ncomms4630
DO - 10.1038/ncomms4630
M3 - Article
C2 - 24710217
AN - SCOPUS:84907304074
SN - 2041-1723
VL - 5
JO - Nature communications
JF - Nature communications
M1 - 3630
ER -